Role of GPR30 in Hepatic Lipid Metabolism

GPR30 在肝脏脂质代谢中的作用

• 批准号: 8917341
• 负责人: DAVID Q WANG
• 金额: $ 18.94万
• 依托单位: SAINT LOUIS UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2014
• 资助国家: 美国
• 起止时间: 2014-09-15 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8917341
• 关键词: Accounting; Address; Age; Basic Science; Bile Acid Biosynthesis Pathway; Bile Acids; Bile fluid; Biliary; CYP7A1 gene; Cell Nucleus; Chemicals; Cholelithiasis; Cholesterol; Cholesterol Homeostasis; Chromosomes, Human, Pair 5; Clinical Research; Conjugated Estrogens; Crystallization; Data; Development; Diet; Endoplasmic Reticulum; Epidemic; Epidemiologic Studies; Epidermal Growth Factor Receptor; Equilibrium; Estrogen Receptors; Estrogen Therapy; Estrogens; Feedback; Female; G-Protein-Coupled Receptors; Gallbladder; Gender; Genes; Hepatic; Hepatocyte; Human; Knowledge; Liver; Liver Failure; Malignant neoplasm of prostate; Maps; Mediating; Membrane; Metabolic; Mission; Molecular; Molecular Genetics; Mucins; Mus; Oral Contraceptives; Outcome; Output; Pathway interactions; Patients; Play; Population; Pre-Clinical Model; Precipitation; Predisposition; Prevalence; Prevention; Preventive Intervention; Publishing; Receptor Signaling; Regulation; Research; Risk; Risk Factors; Role; SRE-2 binding protein; Signal Pathway; Signal Transduction; Solid; Solubility; Steroids; Testing; Therapeutic Intervention; Time; Translating; United States; United States National Institutes of Health; Woman; Work; absorption; base; cell motility; feeding; innovation; lipid metabolism; liquid crystal; men; model design; novel; novel strategies; prevent; rapid growth; response

Epidemiological and clinical studies have found that cholesterol gallstones are more prevalent in women than in men at all ages in every population that has been studied. Accumulated evidence clearly shows that the use of oral contraceptive steroids and conjugated estrogens in women significantly increases the prevalence of cholesterol gallstones. Estrogen therapy to men with prostatic cancer also leads to similar lithogenic effects. These findings show that the increased risk of gallstones in women compared to men is related to differences in how the liver metabolizes cholesterol in response to estrogen. Our published studies have established a central role for estrogen by activating hepatic estrogen receptor α (ERα), but not ERβ, in promoting gallstone formation. However, the mechanisms mediating estrogen’s lithogenic actions on gallstone formation have become more complicated with the identification of a novel estrogen receptor, the G protein-coupled receptor 30 (GPR30). Furthermore, Gpr30 has been mapped to mouse chromosome 5 and is co-localized with Lith18, a new gallstone gene. Our molecular and genetic data support the candidacy of the Gpr30 gene as a compelling gene underlying Lith18. However, identifying the lithogenic mechanism of GPR30 remains a significant challenge because it is not yet fully understood whether GPR30 plays a major role in estrogen-induced gallstones and whether it acts independently of or in conjunction with ERα on inducing cholesterol gallstones. Our central hypothesis is that GPR30 is also involved in estrogen-dependent lithogenic actions, working independently of ERα, as both GPR30 and ERα can work through different pathways to promote the formation of estrogen-induced gallstones. The rationale for the proposed research is that once the particular mechanisms as to how estrogen increases susceptibility to gallstone formation through GPR30 are understood, the key components of estrogen signaling could be manipulated pharmacologically, leading to innovative targets to the treatment of gallstones in women. Guided by our preliminary data, we propose to test this hypothesis by pursuing three specific aims: first, to investigate the phenotypic characterization of GPR30 that determines susceptibility to cholesterol cholelithiasis; second, to study whether GPR30 activation of EGFR leads to the lithogenesis of bile by inhibiting hepatic bile acid synthesis in response to high levels of estrogen; and third, to elucidate the critical role of GPR30 in hepatic hypersecretion of biliary cholesterol and gallbladder hypomotility that accounts for rapid growth of cholesterol crystals. This application is innovative because distinguishing the lithogenic actions of GPR30 from those of ERα and further investigating how estrogen produces lithogenic actions through GPR30 will help elucidate all the molecular mechanisms behind the formation of estrogeninduced cholesterol gallstones. The proposed research is significant because it translates basic research discovery to a pre-clinical model designed to identify novel treatment targets and may provide an efficacious novel strategy for the prevention of gallstones in women and in patients exposed to high levels of estrogen.

流行病学和临床研究发现，胆固醇胆结石在女性中比男性更常见 已研究的所有人群中所有年龄段的男性中，积累的证据清楚地表明使用。 女性服用口服避孕药类固醇和结合雌激素会显着增加女性的患病率 对患有前列腺癌的男性进行雌激素治疗也会导致类似的结石作用。 这些发现表明，与男性相比，女性患胆结石的风险增加与差异有关 我们发表的研究已经确定了肝脏如何代谢胆固醇以响应雌激素。 雌激素通过激活肝脏雌激素受体 α (ERα)（而非 ERβ）在促进胆结石形成中发挥核心作用 然而，介导雌激素对胆结石形成的成石作用的机制已经存在。 随着新型雌激素受体（G 蛋白偶联受体）的鉴定，情况变得更加复杂 30 (GPR30) 此外，Gpr30 已被定位到小鼠 5 号染色体，并与 Lith18（一种基因）共定位。 新的胆结石基因。我们的分子和遗传数据支持 Gpr30 基因作为令人信服的候选基因。 然而，确定 GPR30 的成石机制仍然具有重要意义。 挑战，因为尚未完全了解 GPR30 是否在雌激素诱导的 胆结石以及它是否独立或与 ERα 联合作用来诱导胆固醇胆结石。 我们的中心假设是 GPR30 也参与雌激素依赖性成石作用，发挥作用 独立于 ERα，因为 GPR30 和 ERα 都可以通过不同的途径促进形成 雌激素诱发的胆结石的基本原理是一旦特定的机制。 至于雌激素如何通过GPR30增加胆结石形成的易感性，关键是 雌激素信号传导的成分可以通过药理学的方式进行操纵，从而产生创新的靶点 根据我们的初步数据，我们建议通过以下方式检验这一假设。 追求三个具体目标：首先，研究决定 GPR30 的表型特征 胆固醇性胆石症的易感性；第二，研究EGFR的GPR30激活是否导致 通过抑制高水平雌激素的肝脏胆汁酸合成来形成胆汁；第三， 阐明 GPR30 在肝脏胆汁胆固醇分泌过多和胆囊动力不足中的关键作用 该应用是创新的，因为它区分了胆固醇晶体的快速生长。 GPR30 与 ERα 的成石作用，并进一步研究雌激素如何产生成石作用 通过 GPR30 的作用将有助于阐明雌激素诱导的形成背后的所有分子机制 拟议的研究意义重大，因为它转化了基础研究。 发现旨在识别新治疗靶点的临床前模型，并可能提供有效的治疗方法 预防女性和暴露于高水平雌激素的患者胆结石的新策略。